Arenaviruses are emerging pathogens that are carried by rodents and occasionally transmitted to man with lethal consequences. Our studies focus on Lassa fever virus due to its virulence for human beings. Lassa fever accounts for as many as 300,000 annual infections, and outbreaks have occurred outside the endemic area. In contrast to the well-studied model of arenavirus pathogenesis in the mouse, the virulence of Lassa fever in man, guinea pigs and non-human primates is directly related to viremia, and less related to immune-mediated pathology. Guinea pigs are a potentially useful model for elucidating the pathogenesis of Lassa virus infection and for vaccine and treatment developments. A close relative of Lassa fever virus, Mopeia virus, is not lethal for guinea pigs and monkeys and can protect them from Lassa virus challenge. To determine the genetic basis of Lassa virus virulence we made interspecies virus recombinants between Lassa (LAS) and Mopeia (MOP) viruses. Our studies in guinea pigs show that MOP/LAS reassortant virus is avirulent and non-neurotropic like Mopeia and bears the major protective epitopes of Lassa. We will test the hypothesis that MOP/LAS reassortant virus confers protection from a lethal virus challenge. Our specific aims will be to 1) compare the pathogenicity of reassortant viruses with the pathogenicity of the two parental viruses, LAS and MOP, in guinea pigs; 2) test the ability of the MOP/LAS reassortant to protect animals from lethal challenge with LAS virus. Virulence will be measured in terms of survival, viremia, viral load in tissues, disturbances in clinical chemistry and hemathology. Pro-inflammatory cyto/chemokines, TNF-a and IL-8 will be monitored because in vitro experiments in monocytes/macrophages and endothelial cells show differential effects of LAS and MOP infections on IL-8 and TNF-a expression. Our long range goal is to understand LAS virus pathogenesis and to develop effective treatment and vaccines.